Stem cells and lineage development in the mammalian blastocyst (original) (raw)

Janet Rossant

+ Author Affiliations

- Author Affiliations

Program in Developmental and Stem Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Email: janet.rossant@sickkids.ca

Reproduction, Fertility and Development 19(1) 111-118 https://doi.org/10.1071/RD06125
Published: 12 December 2006

Abstract

The mammalian blastocyst is the source of the most pluripotent stem cells known: embryonic stem (ES) cells. However, ES cells are not totipotent; in mouse chimeras, they do not contribute to extra-embryonic cell types of the trophectoderm (TE) and primitive endoderm (PrE) lineages. Understanding the genetic pathways that control pluripotency v. extra-embryonic lineage restriction is key to understanding not only normal embryonic development, but also how to reprogramme adult cells to pluripotency. The trophectoderm and primitive endoderm lineages also provide the first signals that drive patterned differentiation of the pluripotent epiblast cells of the embryo. My laboratory has produced permanent mouse cell lines from both the TE and the PrE, termed trophoblast stem (TS) and eXtra-embryonic ENdoderm (XEN) cells. We have used these cells to explore the genetic and molecular hierarchy of lineage restriction and identify the key factors that distinguish the ES cell v. the TS or XEN cell fate. The major molecular pathways of lineage commitment defined in mouse embryos and stem cells are probably conserved across mammalian species, but more comparative studies of lineage development in embryos of non-rodent mammals will likely yield interesting differences in terms of timing and details.

Acknowledgments

The author’s own work was supported by the Canadian Institutes of Health Research by both operating grants and a Distinguished Scientist award and by the Stem Cell Network of Centres of Excellence.

References

Adelman, D. M. , Gertsenstein, M. , Nagy, A. , Simon, M. C. , and Maltepe, E. (2000). Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev. 14, 3191–3203.
| Crossref | GoogleScholarGoogle Scholar | PubMed | Kunath T., Strumpf D., Rossant J., and Tanaka S. (2001). Trophoblast stem cells. In ‘Stem Cell Biology’. (Eds D. R. Marshak, R. L. Gardner and D. Gottlieb.) pp. 267–287. (Cold Spring Harbor Laboratory Press: Cold Spring Harbor.)

Kunath, T. , Strumpf, D. , and Rossant, J. (2004). Early trophoblast determination and stem cell maintenance in the mouse: a review. Placenta 25(Suppl. A), S32–S38.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/J.PLACENTA.2004.01.015&atitle=Early trophoblast determination and stem cell maintenance in the mouse: a review.&title=Placenta&date=2004&volume=25&spage=S32&epage=S38&aulast=Kunath&aufirst=T.)

Kunath, T. , Arnaud, D. , Uy, G. D. , Okamoto, I. , and Chureau, C. , et al. (2005). Imprinted X-inactivation in extraembryonic endoderm cell lines from mouse blastocysts. Development 132, 1649–1661.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1242/DEV.01715&atitle=Imprinted X-inactivation in extraembryonic endoderm cell lines from mouse blastocysts.&title=Development&date=2005&volume=132&spage=1649&epage=1661&aulast=Kunath&aufirst=T.)

Kurosaka, S. , Eckardt, S. , and McLaughlin, K. J. (2004). Pluripotent lineage definition in bovine embryos by Oct4 transcript localization. Biol. Reprod. 71, 1578–1582.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1095/BIOLREPROD.104.029322&atitle=Pluripotent lineage definition in bovine embryos by Oct4 transcript localization.&title=Biol. Reprod.&date=2004&volume=71&spage=1578&epage=1582&aulast=Kurosaka&aufirst=S.)

Lake, J. , Rathjen, J. , Remiszewski, J. , and Rathjen, P. D. (2000). Reversible programming of pluripotent cell differentiation. J. Cell Sci. 113, 555–566.
| PubMed | [](OpenURL%5FBaseURL?atitle=Reversible programming of pluripotent cell differentiation.&title=J. Cell Sci.&date=2000&volume=113&spage=555&epage=566&aulast=Lake&aufirst=J.)

Luo, J. , Sladek, R. , Bader, J. A. , Matthyssen, A. , Rossant, J. , and Giguere, V. (1997). Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-β. Nature 388, 778–782.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1038/42022&atitle=Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-β.&title=Nature&date=1997&volume=388&spage=778&epage=782&aulast=Luo&aufirst=J.)

Mak, W. , Baxter, J. , Silva, J. , Newall, A. E. , Otte, A. P. , and Brockdorff, N. (2002). Mitotically stable association of polycomb group proteins eed and enx1 with the inactive X chromosome in trophoblast stem cells. Curr. Biol. 12, 1016–1020.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/S0960-9822%2802%2900892-8&atitle=Mitotically stable association of polycomb group proteins eed and enx1 with the inactive X chromosome in trophoblast stem cells.&title=Curr. Biol.&date=2002&volume=12&spage=1016&epage=1020&aulast=Mak&aufirst=W.)

Martin, G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78, 7634–7638.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1073/PNAS.78.12.7634&atitle=Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.&title=Proc. Natl Acad. Sci. USA&date=1981&volume=78&spage=7634&epage=7638&aulast=Martin&aufirst=G. R.)

Matsuda, T. , Nakamura, T. , Nakao, K. , Arai, T. , Katsuki, M. , Heike, T. , and Yokota, T. (1999). STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J. 18, 4261–4269.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1093/EMBOJ/18.15.4261&atitle=STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells.&title=EMBO J.&date=1999&volume=18&spage=4261&epage=4269&aulast=Matsuda&aufirst=T.)

Mitsui, K. , Tokuzawa, Y. , Itoh, H. , Segawa, K. , Murakami, M. , Takahashi, K. , Maruyama, M. , Maeda, M. , and Yamanaka, S. (2003). The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631–642.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/S0092-8674%2803%2900393-3&atitle=The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells.&title=Cell&date=2003&volume=113&spage=631&epage=642&aulast=Mitsui&aufirst=K.)

Molkentin, J. D. , Lin, Q. , Duncan, S. A. , and Olson, E. N. (1997). Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 11, 1061–1072.
| PubMed | [](OpenURL%5FBaseURL?atitle=Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis.&title=Genes Dev.&date=1997&volume=11&spage=1061&epage=1072&aulast=Molkentin&aufirst=J. D.)

Morrisey, E. E. , Tang, Z. , Sigrist, K. , Lu, M. M. , Jiang, F. , Ip, H. S. , and Parmacek, M. S. (1998). GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 12, 3579–3590.
| PubMed | [](OpenURL%5FBaseURL?atitle=GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo.&title=Genes Dev.&date=1998&volume=12&spage=3579&epage=3590&aulast=Morrisey&aufirst=E. E.)

Mummery, C. , Ward-van Oostwaard, D. , Doevendans, P. , Spijker, R. , and van den Brink, S. , et al. (2003). Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation 107, 2733–2740.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1161/01.CIR.0000068356.38592.68&atitle=Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells.&title=Circulation&date=2003&volume=107&spage=2733&epage=2740&aulast=Mummery&aufirst=C.)

Murakami, A. , Shen, H. , Ishida, S. , and Dickson, C. (2004). SOX7 and GATA-4 are competitive activators of Fgf-3 transcription. J. Biol. Chem. 279, 28 564–28 573.
| PubMed | [](OpenURL%5FBaseURL?atitle=SOX7 and GATA-4 are competitive activators of Fgf-3 transcription.&title=J. Biol. Chem.&date=2004&volume=279&spage=28 564&epage=28 573&aulast=Murakami&aufirst=A.)

Murray, P. , and Edgar, D. (2001). Regulation of the differentiation and behaviour of extra-embryonic endodermal cells by basement membranes. J. Cell Sci. 114, 931–939.
| PubMed | [](OpenURL%5FBaseURL?atitle=Regulation of the differentiation and behaviour of extra-embryonic endodermal cells by basement membranes.&title=J. Cell Sci.&date=2001&volume=114&spage=931&epage=939&aulast=Murray&aufirst=P.)

Nagy, A. , Rossant, J. , Nagy, R. , Abramow-Newerly, W. , and Roder, J. C. (1993). Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1073/PNAS.90.18.8424&atitle=Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.&title=Proc. Natl Acad. Sci. USA&date=1993&volume=90&spage=8424&epage=8428&aulast=Nagy&aufirst=A.)

Nichols, J. , Zevnik, B. , Anastassiadis, K. , Niwa, H. , Klewe-Nebenius, D. , Chambers, I. , Scholer, H. , and Smith, A. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/S0092-8674%2800%2981769-9&atitle=Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.&title=Cell&date=1998&volume=95&spage=379&epage=391&aulast=Nichols&aufirst=J.)

Nichols, J. , Chambers, I. , Taga, T. , and Smith, A. (2001). Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development 128, 2333–2339.
| PubMed | [](OpenURL%5FBaseURL?atitle=Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines.&title=Development&date=2001&volume=128&spage=2333&epage=2339&aulast=Nichols&aufirst=J.)

Niimi, T. , Hayashi, Y. , Futaki, S. , and Sekiguchi, K. (2004). SOX7 and SOX17 regulate the parietal endoderm-specific enhancer activity of mouse laminin α1 gene. J. Biol. Chem. 279, 38 055–38 061.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1074/JBC.M403724200&atitle=SOX7 and SOX17 regulate the parietal endoderm-specific enhancer activity of mouse laminin α1 gene.&title=J. Biol. Chem.&date=2004&volume=279&spage=38 055&epage=38 061&aulast=Niimi&aufirst=T.)

Nishimura, T. , Dunk, C. , Lu, Y. , Feng, X. , Gellhaus, A. , Winterhager, E. , Rossant, J. , and Lye, S. J. (2004). Gap junctions are required for trophoblast proliferation in early human placental development. Placenta 25, 595–607.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/J.PLACENTA.2004.01.002&atitle=Gap junctions are required for trophoblast proliferation in early human placental development.&title=Placenta&date=2004&volume=25&spage=595&epage=607&aulast=Nishimura&aufirst=T.)

Niwa, H. , Miyazaki, J. , and Smith, A. G. (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat. Genet. 24, 372–376.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1038/74199&atitle=Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.&title=Nat. Genet.&date=2000&volume=24&spage=372&epage=376&aulast=Niwa&aufirst=H.)

Notarianni, E. , and Flechon, J. (2001). Parietal endoderm cell line from a rat blastocyst. Placenta 22, 111–123.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1053/PLAC.2000.0592&atitle=Parietal endoderm cell line from a rat blastocyst.&title=Placenta&date=2001&volume=22&spage=111&epage=123&aulast=Notarianni&aufirst=E.)

Odorico, J. S. , Kaufman, D. S. , and Thomson, J. A. (2001). Multilineage differentiation from human embryonic stem cell lines. Stem Cells 19, 193–204.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1634/STEMCELLS.19-3-193&atitle=Multilineage differentiation from human embryonic stem cell lines.&title=Stem Cells&date=2001&volume=19&spage=193&epage=204&aulast=Odorico&aufirst=J. S.)

Palmieri, S. L. , Peter, W. , Hess, H. , and Scholer, H. R. (1994). Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. Dev. Biol. 166, 259–267.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1006/DBIO.1994.1312&atitle=Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation.&title=Dev. Biol.&date=1994&volume=166&spage=259&epage=267&aulast=Palmieri&aufirst=S. L.)

Pera, M. F. , Andrade, J. , Houssami, S. , Reubinoff, B. , Trounson, A. , Stanley, E. G. , Ward-van Oostwaard, D. , and Mummery, C. (2004). Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J. Cell Sci. 117, 1269–1280.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1242/JCS.00970&atitle=Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin.&title=J. Cell Sci.&date=2004&volume=117&spage=1269&epage=1280&aulast=Pera&aufirst=M. F.)

Prelle, K. , Zink, N. , and Wolf, E. (2002). Pluripotent stem cells: model of embryonic development, tool for gene targeting, and basis of cell therapy. Anat. Histol. Embryol. 31, 169–186.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1046/J.1439-0264.2002.00388.X&atitle=Pluripotent stem cells: model of embryonic development, tool for gene targeting, and basis of cell therapy.&title=Anat. Histol. Embryol.&date=2002&volume=31&spage=169&epage=186&aulast=Prelle&aufirst=K.)

Rossant, J. , and Tamara-Lis, W. (1981). Effect of culture conditions in diploid to giant-cell transformation in postimplantation mouse trophoblast. J. Embryol. Exp. Morphol. 62, 217–227.
| PubMed | [](OpenURL%5FBaseURL?atitle=Effect of culture conditions in diploid to giant-cell transformation in postimplantation mouse trophoblast.&title=J. Embryol. Exp. Morphol.&date=1981&volume=62&spage=217&epage=227&aulast=Rossant&aufirst=J.)

Russ, A. P. , Wattler, S. , Colledge, W. H. , Aparicio, S. A. , and Carlton, M. B. , et al. (2000). Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404, 95–99.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1038/35003601&atitle=Eomesodermin is required for mouse trophoblast development and mesoderm formation.&title=Nature&date=2000&volume=404&spage=95&epage=99&aulast=Russ&aufirst=A. P.)

Shamblott, M. J. , Axelman, J. , Wang, S. , Bugg, E. M. , Littlefield, J. W. , Donovan, P. J. , Blumenthal, P. D. , Huggins, G. R. , and Gearhart, J. D. (1998). Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc. Natl Acad. Sci. USA 95, 13 726–13 731.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1073/PNAS.95.23.13726&atitle=Derivation of pluripotent stem cells from cultured human primordial germ cells.&title=Proc. Natl Acad. Sci. USA&date=1998&volume=95&spage=13 726&epage=13 731&aulast=Shamblott&aufirst=M. J.)

Sirard, C. , de la Pompa, J. L. , Elia, A. , Itie, A. , and Mirtsos, C. , et al. (1998). The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev. 12, 107–119.
| PubMed | [](OpenURL%5FBaseURL?atitle=The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.&title=Genes Dev.&date=1998&volume=12&spage=107&epage=119&aulast=Sirard&aufirst=C.)

Soudais, C. , Bielinska, M. , Heikinheimo, M. , MacArthur, C. A. , Narita, N. , Saffitz, J. E. , Simon, M. C. , Leiden, J. M. , and Wilson, D. B. (1995). Targeted mutagenesis of the transcription factor GATA-4 gene in mouse embryonic stem cells disrupts visceral endoderm differentiation in vitro. Development 121, 3877–3888.
| PubMed | [](OpenURL%5FBaseURL?atitle=Targeted mutagenesis of the transcription factor GATA-4 gene in mouse embryonic stem cells disrupts visceral endoderm differentiation in vitro.&title=Development&date=1995&volume=121&spage=3877&epage=3888&aulast=Soudais&aufirst=C.)

Strickland, S. , and Mahdavi, V. (1978). The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 15, 393–403.
| Crossref | GoogleScholarGoogle Scholar | PubMed |[](OpenURL%5FBaseURL?id=doi:10.1016/0092-8674%2878%2990008-9&atitle=The induction of differentiation in teratocarcinoma stem cells by retinoic acid.&title=Cell&date=1978&volume=15&spage=393&epage=403&aulast=Strickland&aufirst=S.)

Strickland, S. , Smith, K. K. , and Marotti, K. R. (1980). Hormonal induction of differentiation in teratocarcinoma stem cells: generation of parietal endoderm by retinoic acid and dibutyryl cAMP. Cell 21, 347–355.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/0092-8674%2880%2990471-7&atitle=Hormonal induction of differentiation in teratocarcinoma stem cells: generation of parietal endoderm by retinoic acid and dibutyryl cAMP.&title=Cell&date=1980&volume=21&spage=347&epage=355&aulast=Strickland&aufirst=S.)

Strumpf, D. , Mao, C.-A. , Yamanaka, Y. , Ralston, A. , Chawengsaksophak, K. , Beck, F. , and Rossant, J. (2005). Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132, 2093–2102.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1242/DEV.01801&atitle=Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst.&title=Development&date=2005&volume=132&spage=2093&epage=2102&aulast=Strumpf&aufirst=D.)

Takito, J. , and Al-Awqati, Q. (2004). Conversion of ES cells to columnar epithelia by hensin and to squamous epithelia by laminin. J. Cell Biol. 166, 1093–1102.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1083/JCB.200405159&atitle=Conversion of ES cells to columnar epithelia by hensin and to squamous epithelia by laminin.&title=J. Cell Biol.&date=2004&volume=166&spage=1093&epage=1102&aulast=Takito&aufirst=J.)

Tanaka, S. , Kunath, T. , Hadjantonakis, A. K. , Nagy, A. , and Rossant, J. (1998). Promotion of trophoblast stem cell proliferation by FGF4. Science 282, 2072–2075.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1126/SCIENCE.282.5396.2072&atitle=Promotion of trophoblast stem cell proliferation by FGF4.&title=Science&date=1998&volume=282&spage=2072&epage=2075&aulast=Tanaka&aufirst=S.)

Thomas, P. , and Beddington, R. (1996). Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6, 1487–1496.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/S0960-9822%2896%2900753-1&atitle=Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo.&title=Curr. Biol.&date=1996&volume=6&spage=1487&epage=1496&aulast=Thomas&aufirst=P.)

Thomson, J. A. , Kalishman, J. , Golos, T. G. , Durning, M. , Harris, C. P. , Becker, R. A. , and Hearn, J. P. (1995). Isolation of a primate embryonic stem cell line. Proc. Natl Acad. Sci. USA 92, 7844–7848.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1073/PNAS.92.17.7844&atitle=Isolation of a primate embryonic stem cell line.&title=Proc. Natl Acad. Sci. USA&date=1995&volume=92&spage=7844&epage=7848&aulast=Thomson&aufirst=J. A.)

Thomson, J. A. , Itskovitz-Eldor, J. , Shapiro, S. S. , Waknitz, M. A. , Swiergiel, J. J. , Marshall, V. S. , and Jones, J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1126/SCIENCE.282.5391.1145&atitle=Embryonic stem cell lines derived from human blastocysts.&title=Science&date=1998&volume=282&spage=1145&epage=1147&aulast=Thomson&aufirst=J. A.)

Tremblay, G. B. , Kunath, T. , Bergeron, D. , Lapointe, L. , Champigny, C. , Bader, J. A. , Rossant, J. , and Giguere, V. (2001). Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERRβ. Genes Dev. 15, 833–838.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1101/GAD.873401&atitle=Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERRβ.&title=Genes Dev.&date=2001&volume=15&spage=833&epage=838&aulast=Tremblay&aufirst=G. B.)

van de Stolpe, A. , Karperien, M. , Lowik, C. W. , Juppner, H. , Segre, G. V. , Abou-Samra, A. B. , de Laat, S. W. , and Defize, L. H. (1993). Parathyroid hormone-related peptide as an endogenous inducer of parietal endoderm differentiation. J. Cell Biol. 120, 235–243.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1083/JCB.120.1.235&atitle=Parathyroid hormone-related peptide as an endogenous inducer of parietal endoderm differentiation.&title=J. Cell Biol.&date=1993&volume=120&spage=235&epage=243&aulast=van de Stolpe&aufirst=A.)

Verheijen, M. H. , Karperien, M. , Karperien, M. , Chung, U. , and van Wijuen, M. , et al. (1999). Parathyroid hormone-related peptide (PTHrP) induces parietal endoderm formation exclusively via the type I PTH/PTHrP receptor. Mech. Dev. 81, 151–161.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/S0925-4773%2898%2900240-8&atitle=Parathyroid hormone-related peptide %28PTHrP%29 induces parietal endoderm formation exclusively via the type I PTH/PTHrP receptor.&title=Mech. Dev.&date=1999&volume=81&spage=151&epage=161&aulast=Verheijen&aufirst=M. H.)

Wang, J. , Mager, J. , Chen, Y. , Schneider, E. , Cross, J. C. , Nagy, A. , and Magnuson, T. (2001). Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat. Genet. 28, 371–375.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1038/NG574&atitle=Imprinted X inactivation maintained by a mouse Polycomb group gene.&title=Nat. Genet.&date=2001&volume=28&spage=371&epage=375&aulast=Wang&aufirst=J.)

Wewer, U. (1982). Characterization of a rat yolk sac carcinoma cell line. Dev. Biol. 93, 416–421.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1016/0012-1606%2882%2990128-2&atitle=Characterization of a rat yolk sac carcinoma cell line.&title=Dev. Biol.&date=1982&volume=93&spage=416&epage=421&aulast=Wewer&aufirst=U.)

Xu, R. H. , Chen, X. , Li, D. S. , Li, R. , Addicks, G. C. , Glennon, C. , Zwaka, T. P. , and Thomson, J. A. (2002). BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat. Biotechnol. 20, 1261–1264.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1038/NBT761&atitle=BMP4 initiates human embryonic stem cell differentiation to trophoblast.&title=Nat. Biotechnol.&date=2002&volume=20&spage=1261&epage=1264&aulast=Xu&aufirst=R. H.)

Yamamoto, H. , Flannery, M. L. , Kupriyanov, S. , Pearce, J. , McKercher, S. R. , Henkel, G. W. , Maki, R. A. , Werb, Z. , and Oshima, R. G. (1998). Defective trophoblast function in mice with a targeted mutation of Ets2. Genes Dev. 12, 1315–1326.
| PubMed | [](OpenURL%5FBaseURL?atitle=Defective trophoblast function in mice with a targeted mutation of Ets2.&title=Genes Dev.&date=1998&volume=12&spage=1315&epage=1326&aulast=Yamamoto&aufirst=H.)

Yamamoto, M. , Saijoh, Y. , Perea-Gomez, A. , Shawlot, W. , Behringer, R. R. , Ang, S. L. , Hamada, H. , and Meno, C. (2004). Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature 428, 387–392.
| Crossref | GoogleScholarGoogle Scholar | PubMed | [](OpenURL%5FBaseURL?id=doi:10.1038/NATURE02418&atitle=Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo.&title=Nature&date=2004&volume=428&spage=387&epage=392&aulast=Yamamoto&aufirst=M.)